A Clinician's Guide to Screening for Symptomatic Mefloquine Exposure and Evaluating Claims of Chronic Neuropsychiatric Effects

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A Clinician’s Guide to Screening for Symptomatic Mefloquine Exposure and Evaluating Claims of Chronic Neuropsychiatric Effects from Mefloquine Poisoning Remington Nevin, MD, MPH, DrPH Elspeth Cameron Ritchie, MD, MPH November 29, 2018 Disclosures • The presenters have the following interests to disclose: • Dr. Nevin serves as consultant and expert witness in criminal and civil cases involving claims of adverse effects from mefloquine • Dr. Ritchie serves as consultant in criminal cases involving claims of adverse effects from mefloquine • The views expressed are those of the presenters and are not necessarily those of the Department of Defence (DoD) or the Department of Veterans Affairs (VA) • PESG and AMSUS staff have no interests to disclose. • This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with AMSUS. PESG, AMSUS, and all accrediting organizations do not support or endorse any product or service mentioned in this activity. Learning Objectives

At the conclusion of this activity, the participant will be able to: 1. Demonstrate methods for screening veterans for symptomatic mefloquine exposure 2. Identify neuropsychiatric effects associated with symptomatic exposure to mefloquine 3. Describe plausible pathophysiologic mechanisms of mefloquine's chronic neuropsychiatric effects 4. Assess the relevance of mefloquine’s chronic neuropsychiatric effects in the diagnosis and management of various psychiatric and neurologic disorders CE/CME Credit

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Background

• Mefloquine developed by the U.S. military as an antimalarial drug – Origins in the Vietnam War • Widespread use during deployments beginning in the 1990s (e.g. Somalia, OIF/OEF) – Hundreds of thousands exposed • Recently deprioritized for use – Followed FDA boxed warning and recognition of chronic neuropsychiatric effects 2013 FDA Boxed Warning Mefloquine Neurotoxicity

• Chronic effects are most parsimoniously explained by idiosyncratic neurotoxicity – In vitro and in vivo evidence – Evidence from structurally-related quinoline drugs • Focal effects within specific brainstem and limbic structures • Symptomatic mefloquine exposure as a risk factor for chronic effects

Reference: Nevin RL. Idiosyncratic quinoline central nervous system toxicity: Historical insights into the chronic neurological sequelae of mefloquine. International journal for parasitology Drugs and drug resistance. 2014;4(2):118-125.

Vignette #1

• 33 year old male, Army intelligence officer, TS clearance • PMH: None • Deployed to Iraq in 2003 • Presented acutely in theater to combat stress control after suffering vivid nightmares, visual hallucinations, panic, persecutory delusions, confusion, and dizziness • Initially diagnosed with combat stress reaction vs. panic attack, attributed to his observing a dead body the day prior • Charged with cowardice and returned to the U.S. • Evaluated by ENT and found to have objective evidence of central vestibular dysfunction • Charges dropped • Medically separated from service for PTSD and vestibular disorder • Awarded 30% rating for service-connected “vestibular dysfunction secondary to adverse reaction” to mefloquine • Awarded 30% rating for service-connected PTSD “with toxic psychosis secondary” to mefloquine • Additional ratings for tinnitus, GERD, and IBS

References: 1. Nevin RL, Ritchie EC. The Mefloquine Intoxication Syndrome: A Significant Potential Confounder in the Diagnosis and Management of PTSD and Other Chronic Deployment-Related Neuropsychiatric Disorders. In: Posttraumatic Stress Disorder and Related Diseases in Combat Veterans. Cham: Springer International Publishing; 2015:257-278; and 2. Nevin RL. Mefloquine and Posttraumatic Stress Disorder. In: Ritchie EC, ed. Textbook of Military Medicine. Forensic and Ethical Issues in Military Behavioral Health. Washington, DC: Borden Institute; 2015:277-296. Screening for Symptomatic Mefloquine Exposure • Screen all Gulf War era and post-9/11 era veterans • White River Mefloquine Instrument - 2 Question (WRMI-2) – Designed to have high sensitivity • Assessment of relevant exposure, not a clinical instrument • A positive exposure screen should prompt taking a focused mefloquine history

Reference: Nevin RL. Screening for Symptomatic Mefloquine Exposure Among Veterans With Chronic Psychiatric Symptoms. Federal Practitioner. 2017;34(3):12-14. WRMI-2

• “Have you ever taken the weekly drug mefloquine (also known as Lariam®) to prevent malaria?" • If yes, “At any time while taking the drug, did you experience abnormal dreams or nightmares, insomnia, anxiety, depression, restlessness, or confusion?”

“Psychiatric symptoms such as insomnia, abnormal dreams/nightmares, acute anxiety, depression, restlessness or confusion have to be regarded as prodromal for a more serious event [emphasis added]” Focused Mefloquine History

• Pre-exposure symptomatology • Confirmed or suspected exposure • Prodromal symptoms • Circumstances of any continued use • Evolution of symptoms • Temporal relation of symptoms to other exposures (e.g. concussive events and traumatic stressors) Vignette #2

• 32 year old male naval officer • PMH: None • Deployed to seas off East Africa in 2009 • Experienced intense nightmares and anxiety early during deployment • Subsequently developed disequilibrium and confusion • Experienced a traumatic event (i.e. enemy gun fire) towards the end of his deployment • Diagnosed with PTSD following his return home • Subsequently evaluated for persistent vertigo; found to have normal MRI of the IACs, hyperactive VOR gains and low VOR phase on RCT, deemed consistent with central vestibulopathy • Suffers persistent insomnia, nightmares, depression, anxiety, dizziness, and poor short-term memory

Reference: Livezey J, Oliver T, Cantilena L. Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine. Drug safety - case reports. 2016;3(1):7. “In the oculomotor, trochlear, an abducent nuclei there was considerable dropping out of nerve cells, degenerative changes in many that remained, and moderate proliferation of microglia and oligodendroglia. A representative field from the oculomotor nucleus is illustrated in Fig. 4. Somewhat slighter changes were observed in the vestibular nuclei, especially in the medial vestibular nucleus”

Reference: Loken AC, Haymaker W. Pamaquine poisoning in man, with a clinicopathologic study of one case. The American journal of tropical medicine and hygiene. 1949;29(3):341-352. “...in doses well below the lethal level [these drugs] produced striking symptoms of central nervous system injury associated with severe lesions in the principal nuclei of the proprioceptive, visual-reflex, and vestibulo cerebellar pathways.…”

Reference: Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. III. The effects of pentaquine, isopentaquine, primaquine, and pamaquine on the central nervous system of the rhesus monkey. Journal of neuropathology and experimental neurology. 1951;10(3):231–56. Medial vestibular nuclei Lateral vestibular nuclei

Control

Plasmocid

Reference: Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. I. Lesions in the Central Nervous System of the Rhesus Monkey Induced by Administration of Plasmocid. J Neuropathol Exp Neurol. 1948;7(4):368–98. Reference: Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. III. The effects of pentaquine, isopentaquine, primaquine, and pamaquine on the central nervous system of the rhesus monkey. J Neuropathol Exp Neurol. 1951;10(3):231-56. “The brain stem structure that we observed to be primarily targeted by mefloquine was the n. gracilis. The n. gracilis is a component of the dorsal column system which transfers proprioceptive signals… Simple clinical neurological exams of humans might also reveal whether the loss of proprioceptive function underpins the vertigo/dizziness seen with some mefloquine-treated patients. It is also important to point out that the mefloquine-induced brain stem injury revealed by silver staining is permanent in nature.”

Reference: Dow G, Bauman R, Caridha D, et al. Mefloquine induces dose-related neurological effects in a rat model. Antimicrobial agents and chemotherapy. 2006;50(3):1045-1053. Vignette #3

• 24 year old male sailor • No past medical history • Deployed to Spain in 2012 on mefloquine • Experienced unease, anxiety, and foreboding, followed by auditory hallucinations, paranoia, and insomnia • Subsequently developed cognitive impairment, tinnitus, disequilibrium, and “wavy” and rotational vertigo • Normal rotary chair testing, enhanced right-sided VEMP, falls on CDP SOTs 5 and 6 that were considered aphysiologic • On specialist referral to ENT, ageotropic torsion then brief rightbeat nystagmus on right DH; geotropic then downbeat nystagmus on left DH; pure downbeat positional nystagmus without fixation in supine head-hanging position, not reversing on sitting, suspicious for brainstem lesion near vestibular nuclei Reference: Nevin RL. Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report. Travel medicine and infectious disease. 2012;10(3):144-151. Vignette #4

• 47 year old male with nightmares, anxiety, dizziness, and episodic “cliff edge” vertigo after mefloquine • Spontaneous upbeating nystagmus suppressed on fixation; borderline slow vertical saccade velocities • Normal MRI and CDP, normal VNG, DH, & calorics; on RCT, VOR borderline low gains, fast nystagmus decay on bidirectional step testing • Considered consistent with a central process Vignette #5

• 37 year old male with nightmares, anxiety, paranoia, panic, photophobia, tinnitus, dizziness, and vertigo after mefloquine in 2002 • On VNG, slow saccade velocities, low gain in counterclockwise OPK, non-fatiguing left beating nystagmus, not stopping with fixation on right DH; on RCT, fast nystagmus decay on counterclockwise testing • Considered consistent with a central process, possibly in the velocity storage mechanism “Confounding” of PTSD and TBI Diagnosis • According to military authors writing for the CDC, mefloquine “confounds the diagnosis and management” of PTSD and TBI • Confounding – Separate causal pathway to outcome – Correlation between exposure and confounder Confounding

Insomnia

Exposure Nightmares to Stressors Depression

Anxiety Confounding

Insomnia

Exposure Nightmares to Stressors Depression

Anxiety

Other Exposure Confounding

Insomnia

Exposure assumed causation Nightmares to Stressors Depression independent causation Anxiety correlation Confounder Confounding

Insomnia

Exposure assumed causation Nightmares to Stressors Depression actual causation? Anxiety correlation Dizziness Mefloquine Vertigo

References: 1. Nevin RL. Mefloquine Exposure May Confound Associations and Limit Inference in Military Studies of Posttraumatic Stress Disorder. Military Medicine. 2017;182(11/12):1757; and 2. Nevin RL. Confounding by Symptomatic Mefloquine Exposure in Military Studies of Post-Traumatic Stress Disorder. Behavioral medicine. 2017. In press. DSM-5 PTSD Criterion H

• The 2013 revision to the DSM added a diagnostic exclusion • Per Criterion H, the symptoms that would otherwise contribute to a PTSD diagnosis cannot be due to the effects of a medication • In practice, symptoms such as nightmares or insomnia that first began with mefloquine use, prior to any trauma, should not contribute towards PTSD diagnostic criteria “Quinism” • Evidence of common signs and symptoms caused by quinoline drugs – Quinine, quinacrine, primaquine, chloroquine, mefloquine, tafenoquine • Evidence of a common etiology and pathophysiology – Focal brainstem and limbic neurotoxic injury • An emerging disorder with significant potential relevance to epidemiology, treatment, and disability compensation Some Quinism “Red Flags”

• Sleep disturbances: severe insomnia, nightmare disorder, central and obstructive apnea • Vestibular symptoms: dizziness, disequilibrium, vertigo, paresthesias • Central visual symptoms: photophobia, accommodative disorder, binocular dysfunction • Panic, agoraphobia, “supermarket syndrome” • Cognitive dysfunction, personality changes, paranoia, psychosis • Esophageal and GI conditions • Neuroendocrine conditions Where to Refer?

• Neurology • ENT / Neuro-otology (rotary chair testing) • Neuro-ophthalmology / Neuro-optometry • Sleep Medicine • Neuropsychological testing • Speech-Language Pathology • WRIISCs and NICoEs Remington L. Nevin, MD, MPH, DrPH The Quinism Foundation P.O. Box 145 White River Junction, VT 05001 [email protected]

Remington L. Nevin, MD, MPH, DrPH Consultant Physician Epidemiologist 5 South Main Street, Suite 322 White River Junction, VT 05001 [email protected]